Small molecule drug can weaken the triggers of neuroinflammation, preclinical review shows

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• Source: The University of Alabama at Birmingham


• Date: 24 Sep,2021

Neuroinflammation may cause worse outcomes in cases of stroke, injuries to the brain or injury, and can increase the severity of neurodegenerative diseases such as ALS, Parkinson’s, or Alzheimer’s. This suggests that reducing neuroinflammation might be an exciting new method to treat neurological disorders and neuropathic pain caused by neuroinflammation.

In a preclinical study , published within the Journal Glia, Peter King, M.D. as well as Burt Nabors, M.D. demonstrate that their small-molecule drug, SRI-42127, has the ability to effectively reduce the triggers for neuroinflammation. The experiments conducted in glial cells cultures and mice are opening the way to test SRI-42127 on models of chronic and acute neurologic injury.

Cells called glial are non-neuronal cells in the Central Nervous System, also known as the CNS that aid in supporting and safeguard neurons. One type that are microglia are brain macrophages that react to infection or injury. “Microglia and astroglia are the most important cells of the nervous system’s central part, which when activated stimulate neuroinflammation through the release of toxic mediators of inflammation such as chemical chemokines and cytokines.” King and Nabors said.

King Nabors and King who are both professors at both the University of Alabama at Birmingham Department of Neurology and Neurology, have worked together for over 25 years to research the ways that neuroinflammation triggers and the role that neuroinflammation plays in neuronal injury, cancer, and degenerative disease.

The researchers say that this study builds upon their previous findings that microglia and astroglia cell depend on an important RNA-binding protein named HuR which protects messenger RNAs that encode mediators of inflammation from degradation and facilitates their transformation into proteins.

Neuroinflammation is triggered when astrocytes and microglia activated in the the spinal column release cytokines as well as chemicals like IL1b IL-6 TNF-a iNOS, CXCL1, and CCL2. The messenger RNAs of these pro-inflammatory signaling proteins have Adenine- and Uridine-rich components known as AREs. They regulate their expression.

King, Nabors, and UAB colleagues have previously demonstrated the fact that HuR, an RNA-regulator protein that binds to AREs has a significant role in regulating production of inflammatory cytokine, making it an important control mechanism in neuroinflammation.

HuR typically resides on the nuclei in the glial cells. But, when the glial cells get activated, HuR moves out of the nucleus to the cell’s cytoplasm which can increase its production of neuroinflammatory cytokines as well as chemicals.

In their previous research, UAB researchers have demonstrated that HuR moves out of the nucleus of astrocytes within the acute CNS disorders spinal column injury and stroke. They also demonstrated that it is able to translocate out of the nucleus microglia during the persistent CNS illness ALS or amyotrophic lateral syndrome.

In addition, the monomer HuR is unable to traverse the nuclear envelope, which acts as a membrane that regulates between the nucleus and cytoplasm. Only HuR dimers, formed by connecting two HuR molecules – are able to move from the nucleus to the in the cytoplasm.

This information allowed collaborative research that was carried out by Southern Research, of Birmingham, Alabama, and UAB by using high-throughput screening to determine the small-molecule drug SRI-42127, which blocks dimerization in HuR.

In the current study King Nabors, King Natalia Filippova, Ph.D. and UAB colleagues examined the significance of SRI-42127’s biological effects with the use of lipopolysaccharide or LPS that stimulates cells of the glial system to start the inflammation process. The UAB researchers discovered that treatment with SRI-42127 reduced HuR transfer from the nucleus into the cell cytoplasm when activated by LPS both in culture as well as in mice. SRI-42127 also significantly reduced inflammation-related mediators such as cytokines IL1b TNF-a, IL-6 and iNOS, along with the chemical chemokines CXCL1 as well as CCL2.

Additionally, SRI-42127 inhibited the activity of microglia in the mouse brain and also slowed down the migration of immune-cell monocytes and neutrophils into the CNS from outside the blood-brain barrier. The infiltration of monocytes and neutrophils can cause inflammation in the brain and the spinal cord. In conclusion, SRI-42127 pierced the blood-brain-interface and reduced neuroinflammatory reactions.

“Our findings,”” King and Nabors said, “underscore HuR’s critical role in stimulating glial activation, and the potential of SRI-42127 as well as different HuR inhibitors in treating neurologic disorders caused through this activity.”

In unpublished research jointly in unpublished work with Robert Sorge, Ph.D. Associate Professor within the Department of Psychology, UAB College of Arts and Sciences, King and Nabors have discovered potential benefits of SRI-42127 on reducing the pain of neuropathic and inflammation, which is caused by neuroinflammation induced by microglial. “This could be an alternative to opioids for treating the pain” They said.

Future clinical treatments will require the use of finesse.

“Therapeutic targeting of glia during CNS diseases is an delicate action since these cells provide neuroplastic and neuroprotective effects, dependent on the stage of recovery CNS injury or the severity of neurodegenerative disease” King and Nabors said. “In the first phase following the injury to the spinal cord, trauma brain injuries or strokes the pro-inflammatory activity of glia causes secondary tissue damage and initiates neural pathways for chronic pain, as opposed to the chronic phase when glia act as a protective. When it comes to neurodegenerative disorders like ALS and Alzheimer’s, glia are also involved in different roles throughout their course through the progression of the illness.”

Co-authors with King, Nabors, and Filippova in the current study, “SRI-42127, a novel small molecule inhibitor of the RNA regulator HuR, potently attenuates glial activation in a model of lipopolysaccharide-induced neuroinflammation,” are Rajeshwari Chellappan, Abhishek Guha, Ying Si, Thaddaeus Kwan, Xiuhua Yang, Anish S. Myneni, Shriya Meesala, and Ashley S. Harms, UAB Department of Neurology.

The funds were provided by National Institutes of Health grants for NS092651 and N111275-01, as well as United States Department of Veterans Affairs grant BX001148.

In their lengthy cooperation, King and Nabors have utilized glioblastoma, which is the most common brain tumor used as a model for disease to examine HuR due to the fact that certain factors that cause neuroinflammation stimulate glioblastoma growth. Nabors has been focusing on the properties of tumor suppressors of SRI-42127, and its potential role for the treatment of the glioblastoma as well as other cancers.